Sensor arrangement

ABSTRACT

A sensor arrangement for determining at least one measurand of a measuring medium includes at least one first sensor with a first sensing element used to record measured values of a first measurand of the measuring medium, a housing having a housing wall which surrounds a housing interior containing the first sensing element, wherein the housing interior contains a medium in particular, a liquid which has a predetermined value of the first measurand.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present divisional application is related to and claims the prioritybenefit of U.S. Nonprovisional patent application Ser. No. 15/279,101,filed on Sep. 28, 2016 and German Patent Application No. 10 2015 116357.8, filed on Sep. 28, 2015, the entire contents of which areincorporated herein by reference.

TECHNICAL FIELD

The present disclosure relates to process sensors, particularly toin-line process sensors for disposable reactors.

BACKGROUND

Sensors are used to monitor biological, biochemical, or pharmaceuticalprocesses. They are used to monitor a wide variety of measurands, suchas flow rate, temperature, pressure, or analytical measurands.Analytical measurands are, for example, concentrations or activities ofsubstances contained in the measuring medium to be monitored orvariables correlated to them. Sensors are often stored in a processplant for long periods of time before they are commissioned. Inpharmaceutical, biological, biochemical, or biotechnological processes,sensors are often sterilized before being used in a process.

Pharmaceutical, biological, biochemical, or biotechnological processesare increasingly being carried out by means of so-called disposableprocess solutions, e.g., in process plants in single-use technology.Such process plants comprise pipelines or reactors which are provided asdisposable containers (otherwise known as disposables or disposablebioreactors, or single use bioreactors or single-use components). Suchdisposable containers can, for example, be flexible containers, e.g.,bags, hoses, or fermenters. Bioreactors or fermenters often have supplyand return lines which can, for example, be provided as hoses. Solidpipe sections can also be used in the supply and return lines. All ofthese disposable containers can be disposed of at the end of a process.In this way, complex cleaning and sterilization processes are avoided.In particular, the use of disposable containers prevents the risk ofcross contamination, thereby increasing process reliability.

The processes performed in the disposable containers run in a closedsystem, i.e., without being connected to the environment outside thedisposable containers. Since sterile conditions are often required, thedisposable containers must be sterilized before the introduction of theprocess media. Gamma radiation is often used for this purpose inbiochemical, biological, biotechnological, and pharmaceuticalapplications. Also, while the processes are running in a disposablefermenter or disposable reactor, foreign substances in particular, germsfrom the environment must be prevented from penetrating the inside ofthe process vessel, so that the process flow is not impaired ordistorted. The same also applies to supply and return lines whichterminate in the disposable fermenter or disposable reactor, or lead outof the disposable fermenter or disposable reactor.

In order to monitor or control processes in such disposable processplants it can, as is the case in conventional process plants, benecessary to measure physical or chemical measurands of the mediacontained in the process vessels. The measurands to be monitored can,for example, be temperature or analytical measurands, such as pH value,cell density, conductivity, optical transmission or absorption, or aconcentration or activity of a chemical substance, e.g., of a specifictype of ion of a specific element or of a specific compound, such as thecontent of dissolved oxygen or CO₂. In biotechnological processes,important measurands can also be so-called nutrient parameters, such asthe glucose, glutamate, or lactose content of the process medium, ormetabolic parameters of the microorganisms used in the processes.

At least some of the aforementioned measurands can be measured by meansof optical sensors, for example: an absorption, transmission, orscattered light intensity and thus a cell density a turbidity; aconcentration of specific chemical compounds present in the processmedium; or a spectrometric or photometric sum parameter can bedetermined by irradiating the measuring medium with measuring radiationand by recording the measuring radiation intensity after interactionwith the medium.

As an alternative to or in addition to optical sensors, electrochemicalin particular, potentiometric sensors can be used, for example, todetermine the pH value or an ion concentration in the process medium.Amperometric sensors for determining the dissolved oxygen content or theCO₂ content, and conductivity sensors that work on a conductive orinductive principle, can also be used.

These sensors can be integrated in the wall of a process vessel in whichthe process medium to be monitored is contained and/or can have asensing element integrated in the wall of such a process vessel. Often,so-called in-line measuring systems are used to monitor measuring mediaflowing through pipelines. As a rule, in-line measuring systems have twoconnections which can, for example, be arranged opposite one another sothat the in-line measuring system can be used in a line of a processplant by having the two connections linked to complementary connectionsin the line.

An in-line measuring system for measuring and monitoring severalmeasurands, which can, for example, be used to monitor measurementparameters of a medium present, or possibly flowing, in a sterile liquidline of a biochemical, biotechnological, or pharmaceutical process, isknown, for example, from U.S. Pat. No. 7,973,923. The sterile liquidline can be a process line of a conventional process plant or a processplant in single-use technology.

The in-line measuring system known from U.S. Pat. No. 7,973,923comprises a flow-through cell with a supply line and a return line whicheach has a connection for linking to a line with process medium flowingthrough it, for example, of a process plant. Furthermore, two sensingelements for recording the values of two mutually different measurands,such as pH value, dissolved oxygen content, CO₂ content, concentrationsof specific ions, conductivity, or temperature, are integrated by meansof connections in the wall of the flow-through cell. The sensingelements integrated in the flow-through cell are in contact with theprocess medium flowing through the flow-through cell directly forrecording measured values. Moreover, the flow-through cell has twomountings for a radiation source module and a radiation receiver module.The radiation source module and the radiation receiver module can beinserted opposite each other into the wall of the flow-through cell byfixing them in the mountings. Both modules each have a transparentwindow for the measuring radiation emitted by the radiation source, sothat the radiation emitted by the radiation source encounters theradiation receiver after passing through the flow-through cell and afterinteraction with the process medium flowing through the flow-throughcell. The radiation receiver is equipped to generate and output anelectrical signal which is dependent upon the received radiationintensity. The signal is a measure of a third measurand which can bedifferentiated from the measurands that are recorded by means of the twosensing elements integrated in the flow-through cell. Therefore, bymeans of the sensing elements integrated in the wall of the flow-throughcell and the optical sensor, measured values of three differentmeasurands of process medium flowing through the flow-through cell canbe recorded.

Before sensors are commissioned in a biotechnological, biochemical, orbiological process plant, in particular of the type described above, thesensor must often be sterilized first, just like all the othercomponents of the process plant. For this purpose, sensors or in-linemeasuring systems can be integrated in a process vessel of the plant andsterilized together with the vessel.

When the sensors undergo a storage period, as a result of thesterilization, and/or if there is a long period of time betweensterilization and commissioning, properties of the sensing elements canchange, which can lead to a change in the respective sensorycharacteristic curve, e.g., to a drift of the zero point. The sensingelements of potentiometric and amperometric sensors frequently comprisemembranes that should ideally be stored in a damp atmosphere to ensurethat the sensor provides reliable measured values immediately from thepoint of commissioning.

In addition to this, sterilization by means of gamma radiation, which isrequired for many biochemical and biotechnological processes, would leadto the destruction of electronic components in the sensors. For thisreason, it is recommended, e.g., in DE 10 2011 080 956 A1, that sensors,or sensing elements integrated in flow-through cells, be arranged asanalog sensing elements in the wall of disposable containers to besterilized, and that they only be detachably connected to an electronicunit comprising non-sterilizable components after sterilization, saidelectronic unit being designed to process the analog measured valuesprovided by the sensing element. The electronic unit can continue to beused after the end of the process and can be connected to a newsterilized disposable sensing element in a different processarrangement. Since the complete measuring chain of the sensor, whichcomprises the sensing element and the electronic unit, is not availableuntil commissioning, a calibration or adjustment directly prior tocommissioning would also be desirable in such cases.

Therefore, in many applications there is a need for an option forstoring sensors or sensing elements in a damp atmosphere and for anefficient calibration and/or verification of sensors shortly before orupon commissioning.

SUMMARY

It is, therefore, the aim of the present disclosure to specify a sensorarrangement and a process that enables one or several sensors to beoperated with sufficient measurement accuracy and measurement quality.

The sensor arrangement according to the present disclosure fordetermining at least one measurand of a measuring medium includes atleast one first sensor with a first sensing element used to recordmeasured values of a first measurand of the measuring medium, and ahousing having a housing wall which surrounds a housing interiorcontaining the first sensing element, wherein the housing interiorcontains a medium in particular, a liquid which has a predeterminedvalue of the first measurand.

Due to the fact that the sensing element is arranged in a self-containedhousing interior, storage in the medium over a long period of time ispossible for example, storage in a damp atmosphere, if the medium is aliquid. Since the medium has a defined value of the measurand, it canalso serve as a calibration medium in addition to its function as astorage medium. In this way, by recording a measured value of the firstmeasurand in the medium contained in the housing interior using thefirst sensing element, it is possible to calibrate or adjust the firstsensor upon commissioning or shortly before commissioning. It is, inparticular, possible to perform a one-point calibration with the help ofthe value of the first measurand recorded by the first sensor. In thecase of sensors that are only slightly chemically, mechanically, orthermally loaded, this type of calibration and/or adjustment based upona single measuring point is often sufficient to identify a change in thesensor in particular, a change in the sensor characteristic curve causedby the storage and/or sterilization of the sensor prior to commissioningand, where applicable, to compensate for it by making adjustments.

The housing and the integrated first sensing element can be sterilizedwith the medium contained therein, e.g., by means of irradiation usinggamma radiation and/or beta radiation. The radiation dose thereby usedis at least 25 kGy, and preferably at least 40 kGy, or even above 50kGy. The medium is preferably selected such that the predetermined valueof the first measurand does not change during this irradiation.

In general, calibration is understood to mean checking the display of ameasuring device against a standard. The deviation between true valueand display value is determined. This step is referred to asverification. The alignment of the display value with the true value isreferred to as adjusting. Here and below, the terms “adjustment,”“verification,” and “calibration” are used within the meaning of thesedefinitions.

The sensor comprises a data processing unit, in whose memory acharacteristic curve is stored and which determines the measured valuesof the first measurand by means of the characteristic curve from themeasuring signals of the first sensing element. For example, the sensingelement can be provided separately from the data processing unit and/ordetachably connected to the data processing unit. In this case, thesensing element has electrical connections which are connected to thedata processing unit via a cable connection for transferring measuredvalues, wherein the sensing element and the data processing unittogether form the sensor. The sensing element records the physicalmeasurand and outputs an analog or digital signal which is dependentupon the measurand, as a raw measured value. In this case, the dataprocessing unit is designed to convert raw measured values obtained viathe cable connection to a measured value of the first measurand in thephysical unit of the measurand by means of the characteristics curve,and to output them.

In one embodiment, the first sensing element has a membrane which is incontact with the medium. Storage in a damp atmosphere is advantageousfor many sensing elements with membranes, such as potentiometric oramperometric sensing elements, so that the medium in this embodiment ispreferably a liquid.

In a further embodiment, the first sensing element can be apotentiometric sensing element which comprises a reference half-cell,wherein the reference half-cell comprises a reference electrolyte whichis in contact with the medium via a crossover, such as a diaphragm, andwherein the medium is a liquid which has the same composition as thereference electrolyte. By preventing concentration gradients in this wayvia the crossover, it can be ensured that the compositions of thereference electrolyte, and of the liquid that serves as storage and/orcalibration medium for the first sensor, do not change, even during longperiods of storage.

The first sensing element can, for example, be a potentiometric pHsensing element with a measuring half-cell comprising a pH glassmembrane and the aforementioned reference half-cell. In this embodiment,the medium contained in the housing interior is advantageously a pHbuffer solution in particular, a phosphate buffer solution with a halideconcentration, such as, a chloride concentration which is consistentwith that of the reference electrolyte of the reference half-cell.

In one embodiment, the sensor arrangement can have at least oneconnection device by means of which the sensor arrangement can beintegrated in a process vessel in particular, by which it can beconnected with one or a plurality of process vessel connectionscomplementary to the connection device. The sensor arrangement,including its housing, can, therefore, be linked to the process vessel.This allows for simultaneous sterilization of the sensor arrangementwith the process vessel, such as by means of the aforementionedradiation doses. Upon commissioning of the sensor arrangement, thehousing that surrounds the housing interior that contains the firstsensing element and closes up towards the process vessel can be removedor be opened up towards the process vessel in such a way that theprocess medium contained in the process vessel can be brought intocontact with the first sensing element to record measured values.

Further, the sensor arrangement comprises at least one second sensorwith a second sensing element arranged inside the housing interior,which is designed to record values of a second measurand which is, inparticular, different from the first measurand of the measuring medium,and wherein the medium contained in the housing interior has apredetermined value of the second measurand.

The second sensor can have a data processing unit analogous to the firstsensor alongside the second sensing element, in whose memory acharacteristic curve is stored, and which determines measured values ofthe second measurand with the aid of the characteristic curve from themeasuring signals of the second sensing element. The sensing element ofthe second sensor can be separate from the data processing unit and/ordetachably linked to the data processing unit. In this case, the secondsensing element has electrical connections for transferring measuredvalues which are linked to the data processing unit via a cableconnection, wherein the second sensing element and the data processingunit together form the second sensor. The second sensing element recordsthe second measurand and outputs an electrical signal, which isdependent upon the second measurand, as a raw measured value. In thiscase, the data processing unit is designed to convert raw measuredvalues obtained via the cable connection by means of the characteristiccurve to a measured value of the second measurand in the physical unitof the measurand. The data processing units of the first and secondsensors can be realized in a single device, such as a multi-channeltransformer.

In an embodiment, the sensor arrangement is designed as a prefabricatedin-line measuring system, wherein the housing is designed as aflow-through cell having a cuvette, a supply line terminating in thecuvette, and a return line terminating in the cuvette, wherein, at theend facing away from the cuvette, the supply line and the return lineeach has a connection which closes the flow-through cell of theprefabricated in-line measuring system liquid-tight and which can belinked to a process vessel in particular, a medium service line andwherein the first sensing element is integrated in the flow-through cellin particular, in the cuvette.

The prefabricated in-line measuring system for determining at least onemeasurand of a measuring medium therefore includes: a flow-through cellhaving a cuvette, a supply line terminating in the cuvette, and a returnline terminating in the cuvette, wherein, at the end facing away fromthe cuvette, the supply line and the return line each has a connectionwhich closes the flow-through cell of the prefabricated in-linemeasuring system liquid-tight and which can be linked to a processvessel in particular, a medium service line; a first sensor with a firstsensing element used to record values of a first measurand of themeasuring medium, wherein the first sensing element is integrated in theflow-through cell in particular, in the cuvette; and a medium containedin the flow-through cell in particular, the cuvette filling the supplyline and the return line, which has a predetermined value of the firstmeasurand.

The supply line terminating in the cuvette and the return lineterminating in the cuvette can be designed as hoses. They can haveconnections serving as sterile connectors on the ends facing away fromthe cuvette. Such sterile connectors are designed to be linked tocomplementary sterile connectors of the process line in which thein-line measuring system is to be used, such as hose lines in biologicalor biotechnological process plants, so as to create a mechanicalconnection between the hose line and the supply line or the return lineof the flow-through cell. The sterile connectors and their complementarycounterparts arranged in the lines of the process plant also have meansof closure which ensure sterile closure of the supply and return linesor the process line. By activating the means of closure, after theconnectors have been mechanically connected to their correspondingcomplementary counterparts of the process line, a fluid communicationcan be established between the process line and the return line, or theprocess line and the supply line. These types of sterile connectors arecommercially available.

Further, the in-line measuring system can comprise at least one secondsensor with a second sensing element, which is designed to record valuesof a second measurand of the measuring medium, wherein the mediumcontained in the flow-through cell also has a predetermined value of thesecond measurand.

In such an embodiment, the second sensor can have a data processing unitanalogous to the first sensor alongside the second sensing element, inwhose memory a characteristic curve is stored, and which determinesmeasured values of the second measurand with the aid of thecharacteristic curve from the measuring signals of the second sensingelement. The sensing element of the second sensor can be separate fromthe data processing unit and/or detachably linked to the data processingunit. In this case, the second sensing element has electricalconnections for transferring measured values which are linked to thedata processing unit via a cable connection, wherein the second sensingelement and the data processing unit together form the second sensor.The second sensing element records the second measurand and outputs anelectrical signal, which is dependent upon the second measurand, as araw measured value. In this case, the data processing unit is designedto convert raw measured values obtained via the cable connection bymeans of the characteristic curve to a measured value of the secondmeasurand in the physical unit of the measurand. The data processingunits of the first and second sensors can be realized in a singledevice, such as a multi-channel transformer.

The first and the second sensing element can be arranged in the wall ofthe flow-through cell in particular, of the cuvette in such a way that,for example, by means of an adapter, at least one immersed section ofthe first sensing element and an immersed section of the second sensingelement intended to be in contact with the measuring medium are locatedinside the flow-through cell in particular, the cuvette.

The medium contained in the flow-through cell can be a liquid whichessentially fills the supply line, return line, and the cuvette, so thatthe first and second sensing elements are in contact with the liquid forrecording a value of the first and the second measurands.

In a further embodiment of the in-line measuring system, the firstsensor is a pH sensor, and the second sensor is a conductivity sensor.The pH sensor can, for example, be a potentiometric sensor, and thesecond sensor can be an inductive or conductive conductivity sensor.Other variables which can be considered as first or second measurandsare, for example, CO₂ content, ion concentrations, dissolved oxygencontent, and glucose content.

In such an embodiment, the medium can be an aqueous solution which has apredetermined conductivity resulting from its composition of between 10μS/cm and 300 mS/cm alternately, between 10 μS/cm and 50 mS/cm and whichalso, as a result of the composition of the liquid, has a predeterminedpH value of between 3 and 9, alternately, between 6 and 8.

The aqueous solution can, for example, comprise a buffer system inparticular, a phosphate buffer with a phosphate concentration of 0.01 to0.5 mol/L, such as between 0.01 and 0.05 mol/L. In addition, thesolution can contain sodium chloride and/or potassium chloride. If thesolution contains only sodium chloride, its concentration can be between0.01 and 3.5 mol/L e.g., between 0.1 and 0.2 mol/L. If the solutioncontains only potassium chloride, its concentration can likewise bebetween 0.01 and 3.5 mol/L e.g., between 0.1 and 0.2 mol/L. If thesolution contains both sodium chloride and potassium chloride, itsoverall concentration can be between 0.01 and 3.5 mol/L e.g., between0.1 and 0.2 mol/L. For example, the solution can be a phosphate-bufferedsaline solution with 0.01 mol/L phosphate in the buffer systemH₂PO₄—/HPO₄ ²⁻ and an NaCl concentration of 0.01 to 3.5 mol/L or between0.01 and 0.05 mol/L.

The cuvette can have a wall which includes a first wall section which istransparent to measuring radiation of a predetermined wavelength or of apredetermined wavelength range in particular, to measuring radiation ofthe UV spectral range, of the visible spectral range, or of the IRspectral range and which includes a second wall section facing the firstwall section and essentially running parallel to it, which istransparent to the measuring radiation. For example, the cuvette canhave a window, or the cuvette in its entirety can consist of a materialthat is transparent to the measuring radiation. This embodiment of thecuvette allows the measuring radiation to radiate through thetransparent wall sections and through the medium contained in thecuvette. The intensity of the measuring radiation after passing throughthe cuvette or after diffusing in the cuvette allows thespectrometrically or photometrically recordable measurands, e.g.,concentrations of specific substances, cell densities, or turbidity, tobe determined. A radiation source and a radiation receiver can bemechanically coupled to the wall of the flow-through cell from outside.

The prefabricated in-line measuring system can, for example, in anadvantageous embodiment, further have an optical sensor for recording athird measurand, which is, in particular, different from the first orsecond measurand, and which includes a radiation source and a radiationreceiver, wherein the radiation source is arranged in such a way inrelation to the cuvette that measuring radiation emitted by theradiation source enters the cuvette through a first section of a wall ofthe cuvette which is transparent to the measuring radiation, and whereinthe radiation receiver is arranged in such a way in relation to theradiation source and in relation to the cuvette that the measuringradiation encounters the radiation receiver through the first or asecond section of the wall of the cuvette which is transparent to themeasuring radiation. The third measurand can, alternatively, also be thesame measurand as the first or the second measurand.

One or a plurality of light-emitting diodes or one or a plurality oflaser diodes can be considered as a radiation source. One or a pluralityof photodiodes, a photodiode array, or a CCD array or a CCD line canserve as a radiation receiver.

The radiation source and the radiation receiver can, for example, asdescribed in U.S. Pat. No. 7,973,923, be arranged respectively in aradiation source module and a radiation receiver module. These modulescan each comprise a housing which can be attached to the flow-throughcell, inside which are arranged the radiation source or the radiationreceiver, and electrical or electronic circuits for operating theradiation source or for generating and outputting an electrical signalwhich is used as a raw measured value and which is dependent upon theintensity of the radiation encountering the receiver. Further, theoptical sensor can comprise a data processing unit which determines andoutputs a value of the third measurand with the aid of the raw measuredvalue received by the receiver.

In such an embodiment, the radiation source and the radiation receivercan also be accommodated in an individual housing which includes arecess in which the flow-through cell in particular, the cuvette of theflow-through cell can be arranged. In this embodiment, the housing has afirst window through which the measuring radiation of the radiationsource can exit the housing and a second window in particular, facingthe first window through which measuring radiation can re-enter thehousing after passing through an optical path leading through therecess. The sections of the wall of the cuvette which are transparent tothe measuring radiation can be aligned flush with the windows, so thatthe measuring radiation also penetrates the cuvette along the opticalpath running between the windows.

In this embodiment, the medium contained in the flow-through cell canalso have a value of the third measurand which is predetermined by itscomposition. The third measurand can be an absorption or transmission,or a turbidity or a cell density.

Advantageously, the medium in the wavelength range of the measuringradiation has an absorption between 0 cm⁻¹ and 0.1 cm⁻¹ preferably, ofless than 0.02 cm⁻¹. This is the case, for example, with theaforementioned aqueous phosphate-buffered NaCl and/or KCl solution.

The medium can be a liquid which essentially fills the supply line,return line, and the cuvette, so that an optical measurement pathrunning between the radiation source and the radiation receiver runsthrough the liquid.

The present disclosure also includes a method for commissioning a sensorarrangement in particular, a sensor arrangement in accordance with oneof the previously described embodiments which has a housing wallsurrounding a housing interior, wherein the method includes: therecording of a value of a first measurand of a medium contained in theclosed housing interior, which has a predetermined value of the firstmeasurand, by means of a first sensing element of a first sensor,wherein the first sensing element is arranged in the housing interior;and the performance of a calibration and/or verification and/oradjustment of the first sensor with the aid of the recorded value of thefirst measurand.

The method can further comprise the linking of the sensor arrangementwith a process vessel. This process step can be carried out after therecording of the first measurand by means of the first sensing elementof the first sensor and the performance of the calibration. This isconceivable, for example, if the sensing element is stored for a longerperiod in the medium and is calibrated and/or verified and/or adjustedin the same medium shortly before commissioning and is then integratedand commissioned in a process plant for carrying out process monitoring.

Alternatively or additionally, the sensor arrangement, including thehousing, is mechanically linked with the process vessel before therecording of a value of the first measurand of the medium contained inthe closed housing interior and before the calibration, verification,and/or adjustment of the first sensor is carried out. This isadvantageous, for example, in applications in disposable processsolutions in which the sensor arrangement, with the housing and themedium contained therein serving both as storage and as calibrationmedium, is integrated in a disposable process vessel and sterilizedtogether with the same, and then commissioned after a longer storageperiod. In this way, the calibration and/or verification and/oradjustment can be carried out after the storage period shortly before orupon commissioning of the disposable process vessel and the sensorarrangement integrated therein.

The method can further comprise: the recording of a value of a secondmeasurand of the medium contained in the housing which is closed withrespect to the process vessel, with the medium having a predeterminedvalue of the second measurand, by means of a second sensing element of asecond sensor, wherein the second sensing element is arranged in thehousing interior, and the performance of a calibration and/orverification, and/or adjustment of the second sensor with the aid of therecorded value of the second measurand.

In a further process step which, depending upon the application, cantake place before the sensor arrangement is linked to the process vesselor not until after calibration and/or adjustment of the first sensor,and, possibly, of a second and/or additional sensors of the sensorarrangement, a fluid communication is established between the housinginterior and the process vessel.

Advantageously, the sensor arrangement is designed as a prefabricatedin-line measuring system in accordance with one of the embodimentsdescribed above.

The present disclosure also includes a method for commissioning such anin-line measuring system having a flow-through cell, a cuvette, a supplyline terminating in the cuvette, and a return line terminating in thecuvette, wherein, at the end facing away from the cuvette, the supplyline and the return line each has a connection, e.g., a sterileconnector, which closes the flow-through cell of the prefabricatedin-line measuring system liquid-tight and which can be linked to aprocess vessel in particular, a medium service line wherein the methodincludes: mechanical linking of the connection closing the supply linewith a first connection complementary to this connection of the processvessel and of the connection closing the return line with a secondconnection complementary to this connection of the process vessel; therecording of a value of a first measurand of a medium contained in theflow-through cell, which is still closed with respect to the processvessel, said medium having a predetermined value of the first measurand,by means of a first sensing element of a first sensor which isintegrated in the flow-through cell in particular, in the cuvette, andthe performance of a calibration and/or verification and/or anadjustment of the first sensor with the aid of the recorded value of thefirst measurand.

The performance of the calibration can include the step of the recordingof a measured value of the first measurand of the medium as currentcalibration measured value by means of the first sensing element, andthe comparison of the calibration measured value with the previouslyknown value of the first measurand of the medium.

The performance of the adjustment can include the steps: the recordingof a measured value of the first measurand of the medium as currentcalibration measured value by means of the first sensing element; thecomparison of the calibration measured value with the previously knownvalue of the first measurand of the medium; and the updating of acalculation method or characteristic curve in a memory allocated to thefirst sensing element, which is used to determine a measured value froma measuring signal of the first sensing element, with the aid of thecomparison.

The method can further include: the recording of a value of a secondmeasurand of the medium contained in the flow-through cell, which isstill closed with respect to the process vessel, said medium having apredetermined value of the second measurand, by means of a secondsensing element which is integrated in the flow-through cell inparticular, in the cuvette, and the performance of a calibration and/orverification and/or adjustment of the second sensor with the aid of therecorded value of the second measurand.

A calibration and or an adjustment of the second sensor can be performedin the same way as previously described for the first sensor.

The method can further include: the recording of a value of a thirdmeasurand by means of an optical sensor which includes a radiationsource and a radiation receiver, wherein the radiation source emitsmeasuring radiation which enters a cuvette through a first section of awall of the cuvette which is transparent to the measuring radiation, andpasses through the medium and exits the cuvette again through a secondsection of the wall of the cuvette which is transparent to the measuringradiation, and encounters the radiation receiver, which generates anelectrical signal which is dependent upon the intensity of the measuringradiation encountering the radiation receiver, and the performance of acalibration and/or verification and/or an adjustment of the opticalsensor with the aid of the recorded value of the third measurand.

A calibration and or an adjustment of the optical sensor can beperformed analogously to that previously described for the first sensor.

The method can further include the establishment of a fluidcommunication between the supply line, the return line, and the processvessel.

The medium contained in the housing or, if the housing is designed as aflow-through cell, the medium contained in the flow-through cell, canrun off into the process vessel, e.g., through the return line of theflow-through cell, after the fluid communication has been established.To monitor a medium flowing through the process vessel, said medium canbe fed through the flow-through cell. If the sensor arrangement or thein-line measuring system is used in a biotechnological or biochemicalprocess that is to be kept sterile, it is therefore advantageous for thesections of the flow-through cell communicating with the process vesselby the connection using sterile connectors and the medium contained inthe flow-through cell to be sterile or to be sterilized in advance forexample, by means of irradiating with gamma radiation.

The present disclosure is described in detail below with reference tothe exemplary embodiments illustrated in the figures.

BRIEF DESCRIPTION OF THE DRAWINGS

The present disclosure is explained in further detail below on the basisof the exemplary embodiments shown in the figures.

FIG. 1 shows a schematic longitudinal diagram of a flow-through cellwith two integrated electrochemical sensors, according to an exemplaryembodiment of the present disclosure.

FIGS. 2A, 2B and 2C show exemplary embodiments the flow-through cellaccording to FIG. 1 with an additional optical sensor according to thepresent disclosure.

DETAILED DESCRIPTION

FIG. 1 shows a schematic diagram of an in-line measuring system 1 with aflow-through cell 10 having a cuvette 2, a supply line 3 terminating inthe cuvette 2, and a return line 4 terminating in the cuvette 2. Thecuvette 2 can, for example, consist of a plastic; similarly, the supplyline 3 and the return line 4 can consist of a plastic. The supply line 3and the return line 4, as in the example shown here, can be flexiblehose lines. The supply line 3 and the return line 4 are closed so as tobe sterile by means of a sterile connector 5, 6 on their respective endsfacing away from the cuvette 2. The sterile connectors 5, 6 have lockingmeans by means of which they can be mechanically linked withcomplementary sterile connectors 7, 8 of a liquid line of a processplant, e.g., of a peripheral line of a fermenter or reactor. In thisway, the in-line measuring device 1 can, for example, be linked with itssupply line 3 to a first section 9 of a process line, and, with itsreturn line 4, to a second section 11 of a process line and thus be usedin the process line. Even after the mechanical linking of the sterileconnectors 5, 7, 6, and 8, the flow-through cell is still closedliquid-tight and so as to be sterile with respect to the process line bymeans of the membranes 12, 13, 14, and 15. To establish a fluidcommunication between the flow-through cell 2 and the process line, themembranes 12, 13, 14, 15 are pulled out of the linked connectors.

Two sensing elements 16, 17 are integrated in the wall of the cuvette 2.In the present example, the first sensing element 16 is a pH sensingelement, and the second sensing element 17 is a conductivity sensingelement. Both sensors have connections 18, 19 via which they aredetachably connected to a separate electronic unit 20, which can, forexample, be a multi-channel transducer. The electronics unit 20 can havemeans for digitizing an electrical measuring signal provided by thesensors 16, 17, as well as a data processing unit, which is designed toprocess the digital signals. The processing includes, in particular, thedetermination of measured values of the measurands, pH value, andconductivity from the raw measured values provided by the sensingelements. In the present example, both sensing elements 16, 17 arelinked to a single electronics unit 20. In an alternative embodiment itis, of course, possible for a dedicated electronics unit to be assignedto each sensing element. Similarly, it is possible for the sensingelements to be designed to already output digital measuring signals tothe electronics unit.

A medium 21 filling the cuvette 2, the supply line 3, and the returnline 4 is contained in the flow-through cell 10, said medium having aknown pH value predetermined by its composition and a correspondinglyknown conductivity. The first sensing element 16 has a sensor element,such as a pH-sensitive membrane, which has to be brought into contactwith a measuring medium to record pH measured values. The sensingelement 16 is designed to generate and output an electrical signal whichis dependent upon the pH value of the measuring medium in contact withthe sensor element. For example, the sensing element 16 can be apotentiometric sensing element which outputs a voltage dependent uponthe pH value. The medium 21 contained in the cuvette 2 in the presentcase fills the cuvette 2 to the extent that the sensor element of thesensing element 16 is in contact with the medium 21 and can thereforerecord a pH measured value of the medium 21.

The second sensing element 17 also has a section specifically forcontact with a measuring medium for recording conductivity measuredvalues. In the present example, the immersion area of the sensingelement 17 includes electrodes for a conductive conductivitymeasurement. In the present case, the cuvette 2 is filled by the medium21 to such an extent that the immersion area of the second sensingelement is in contact with the medium 21 to record a conductivitymeasured value.

In the present example, it is possible to sterilize the flow-throughcell 10 with the medium 21 contained therein and the sensing elements16, 17 before their use in the process line, e.g., by means ofirradiation with gamma radiation. In this way, all sections of theflow-through cell 10 and the sensing elements 16, 17, which cansubsequently come into contact with a process medium flowing through theprocess line in which the in-line measuring device is used, can besterilized.

FIGS. 2A-C shows a schematic representation depicting the in-linemeasuring system 1 described with the aid of FIG. 1, with an additionaloptical sensor 22. For purposes of clarity, the first and the secondsensing elements 16, 17 are not shown in FIGS. 2A-C.

The optical sensor 22 is designed to record absorption or transmissionmeasured values of measuring radiation irradiated through the cuvette 2.The sensor 22 has a housing that has a recess on a front side 24, inwhich the cuvette 2 can be inserted. FIG. 2A shows the optical sensor 22separated from the flow-through cell 10, while FIG. 2B shows the sensor22 with the cuvette 2 inserted in the recess 24. The housing of theoptical sensor 22 has windows 25 on two opposing walls, said windowsbeing flush with the transparent wall sections of the cuvette 2 when thecuvette 2 is inserted.

A radiation source 26 in the present example, a UV light-emitting diodeis arranged inside the housing of the sensor 22 (FIG. 2C). Inside thehousing of the sensor 22, there is also a radiation receiver which isdesigned as a photo diode (not visible in FIG. 2C). The radiation source26 and the radiation receiver are arranged in the housing such that theradiation emitted by the radiation source 26 escapes as measuringradiation through one of the windows 24 arranged in the housing wall,passes through the cuvette 2, and encounters the radiation receiverafter entering through the opposite window. Optical elements and/orlight conductors can be provided for this purpose for beam formation andcontrol. The wall sections of the cuvette 2 which are flush with thewindows are transparent to the measuring radiation UV radiation in thepresent example so that the radiation intensity of the measuringradiation encountering the radiation receiver is essentially determinedby the absorption of a measuring medium contained in the cuvette 2.Depending upon the impinging radiation intensity, the radiation receiverdesigned as a photo diode generates an electrical digital or analogsignal, which can be output via the line 23 to an electronics unit. Inthe present example, the sensor 22 is linked to the electronics unit 20(FIG. 1) via the line 23, which thus records and processes the measuringsignals, both from the sensing elements 15 and 16 integrated in theflow-through cell 10 and from the optical sensor 22. In the presentcase, the electronics unit 20 is designed to determine an absorptionmeasured value from the raw electrical signal generated by the radiationreceiver with the aid of a calculation rule based upon the Beer-LambertLaw.

In the present example, the medium 21 filling the flow-through cell 10has an absorption of below 0.02 for the measuring radiation of theoptical sensor 22. It can, therefore, be used to calibrate or adjust orzero balance the optical sensor 22.

The electronics unit 20 is designed for the purpose of performing in themedium 21 a calibration and/or adjustment and/or verification of thesensing elements 16, 17 and of the optical sensor 22 prior toestablishing a fluid communication between the flow-through cell 10 andthe process line by removing the membranes 12, 13, 14, and 15.

For the calibration, the electronics unit 20 triggered, for example, bymeans of an input by operating personnel when commissioning the devicerecords a pH measured value by means of the first sensing element 16, aconductivity measured value by means of the second sensing element 17,and an absorption measured value for the medium 21 by means of theoptical sensor 22. To determine measured values from the measuringsignals supplied by the sensing elements 16, 17 and the sensor 22,calibration functions or characteristic curves are saved in theelectronics unit, e.g., in the form of a calculation rule or a table,with the aid of which the electronics unit 20 determines a correspondingvalue for the measurand with the correct physical units, e.g., a pHmeasured value, from a measuring signal, e.g., a voltage value.

The actual values of these measurands in the medium 21, which aredictated by the composition of said medium, are stored in a memory ofthe electronics unit 20. For verification purposes, the electronics unit20 compares the measured values determined from the recorded measuringsignals with the stored values.

The electronics unit 20 can also perform an adjustment. To this end, theelectronics unit 20, with the aid of the comparison of the measuredvalues determined by means of the sensing elements 16, 17 and theoptical sensor 22 with the stored values for the correspondingmeasurands, determines an adjustment value with which the measuredvalues determined in the future with the aid of the stored calculationrules, e.g., by multiplication or division, are adjusted respectively.Alternatively, the electronics unit can adjust the stored calculationrules, e.g., the calibration functions, accordingly.

The composition of the medium 21 is to be selected in accordance withthe measurands to be recorded by the sensing elements or the opticalsensor in such a way that it has stable, predetermined values for themeasurands to be recorded, even after sterilization. In the presentexample, in which the measurands are pH value, conductivity, andabsorption, a suitable multi-standard medium of this type is an aqueousbuffer solution with defined conductivity and an absorption close tozero in particular, smaller than 0.02 for UV radiation, such as in a UVrange that is typically used for the photometric determination ofbiological molecules that is, between 230 and 280 nm.

A phosphate buffer solution has proved to be suitable for a combinationof the measurands pH value, conductivity, and absorption in thespecified UV range. The solution may also contain sodium chloride orpotassium chloride, if required. Phosphate buffer systems are frequentlyused in biological applications and can be produced using purelyinorganic components which do not demonstrate absorption in thewavelength range of the measuring radiation that is, between 230 and 280nm. NaCl and KCl solutions also demonstrate sufficiently low absorptionin the UV range between 230 and 280 nm that is, an absorption below0.02. Therefore, a phosphate-buffered saline solution with a phosphateconcentration in the buffer system H₂PO₄—/HPO₄ ²⁻ of 0.01 mol/L isparticularly suitable. In order to reliably ensure that the buffercapacity is sufficient, even when minimal interaction of the solutionwith the materials in the flow-through cell occurs, a higher phosphateconcentration of 0.025 mol/L to 0.05 mol/L can also be selected. Thisphosphate buffer solution can additionally contain physiologicalconcentrations of NaCl and/or KCl, wherein the overall concentration ofKCl and NaCl can be between 0.1 to 0.2 mol/L. Such a solution has a pHvalue of 7.4 and a conductivity of 10 to 30 mS/cm.

Claimed is:
 1. A sensor arrangement for determining a measurand of ameasuring medium, comprising: a first sensor with a first sensingelement configured to record values of a first measurand of acalibration medium; and a housing having a housing wall defining ahousing interior, the housing interior containing the first sensingelement and the calibration medium having a predetermined value of thefirst measurand; a membrane fluidly separating the calibration mediumand an exterior of the housing, wherein the membrane is removable toestablish fluid communication between the sensor arrangement and aprocess vessel; wherein the sensor arrangement is configured to bemechanically linked to a process vessel without establishing fluidcommunication between the sensor arrangement and the process vessel;wherein a value of the first measurand of the calibration medium isrecorded by means of the first sensing element before establishing fluidcommunication between the sensor arrangement and the process vessel;wherein a calibration, and/or verification, and/or an adjustment of thefirst sensor using the recorded value of the first measurand isperformed prior to establishing fluid communication between the sensorarrangement and the process vessel.
 2. The sensor arrangement accordingto claim 1, wherein the first sensing element is a potentiometricsensing element comprising a reference half-cell, wherein the referencehalf-cell includes a reference electrolyte in contact with thecalibration medium via a crossover, and the calibration medium is aliquid having the same composition as the reference electrolyte.
 3. Thesensor arrangement according to claim 1, wherein the first sensingelement is a potentiometric pH-sensing element including a measuringhalf-cell having a pH glass membrane.
 4. The sensor arrangementaccording to claim 1, the sensor arrangement further comprising: atleast one process vessel connection device structured to enable thesensor arrangement to be integrated in a process vessel or to be linkedto one or a plurality of process vessel connections.
 5. The sensorarrangement according to claim 4, wherein the housing is removable fromthe sensor arrangement, or a link between the housing interior and theprocess vessel can be created, so that at least the first sensingelement can be brought into contact with a process medium contained inthe process vessel.
 6. The sensor arrangement according to claim 1, thesensor arrangement further comprising a second sensor with a secondsensing element, the second sensing element disposed inside the housinginterior, the second sensor configured to record values of a secondmeasurand of the calibration medium different from the first measurand,wherein the calibration medium has a predetermined value of the secondmeasurand.
 7. The sensor arrangement according to claim 1, wherein thehousing is embodied as a flow-through cuvette and the first sensingelement is disposed in the cuvette, the sensor arrangement furthercomprising: a supply line, the supply line having a proximal endterminating in the cuvette and a distal end including a liquid-tightclosure; a return line, the return line having a proximal endterminating in the cuvette and a distal end including a liquid-tightclosure, wherein, each the supply line and the return line areconnectable to a process vessel via the distal ends.
 8. The sensorarrangement according to claim 7, the sensor arrangement furthercomprising a second sensor with a second sensing element configured torecord values of a second measurand of the calibration medium differentfrom the first measurand, the second sensing element disposed in thecuvette, wherein the calibration medium has a predetermined value of thesecond measurand.
 9. The sensor arrangement according to claim 8,wherein the first and the second sensing elements are disposed in thewall of the cuvette such that at least one immersed section of the firstsensing element and an immersed section of the second sensing elementintended to be in contact with the calibration medium are located insidethe cuvette.
 10. The sensor arrangement according to claim 8, whereinthe calibration medium is a liquid that fills the supply line, returnline, and the cuvette such that the first and second sensing elementsare in contact with the calibration medium.
 11. The sensor arrangementaccording to claim 8, wherein the first sensor is a potentiometric pHsensor and the second sensor is a conductivity sensor.
 12. The sensorarrangement according to claim 11, wherein the calibration medium is anaqueous solution having a predetermined conductivity between 10 μS/cmand 300 mS/cm, and having a predetermined pH value between 3 and
 9. 13.The sensor arrangement according to claim 12, wherein the aqueoussolution comprises a phosphate buffer with a concentration of 0.01 to0.5 mol/L of phosphate and a total of 0.01 to 3.5 mol/L of sodiumchloride and/or potassium chloride.
 14. The sensor arrangement accordingto claim 7, wherein the cuvette comprises a first wall section and asecond wall section facing the first wall section and runningsubstantially parallel to the first wall section, the first wall sectionand the second wall section being transparent to measuring radiation ofa predetermined wavelength range.
 15. The sensor arrangement accordingto claim 14, the sensor arrangement further comprising an optical sensorconfigured to record values of a third measurand different from thefirst measurand and the second measurand, the optical sensor including aradiation source and a radiation receiver, wherein the radiation sourceand the radiation receiver are disposed such that measuring radiationemitted by the radiation source passes through the first wall sectionand subsequently the second wall section and is received by theradiation receiver.
 16. The sensor arrangement according to claim 15,wherein the calibration medium has a predetermined value of the thirdmeasurand.
 17. The sensor arrangement according to claim 16, wherein thecalibration medium in the wavelength range of the measuring radiationhas an absorption of less than 0.1 cm⁻¹.
 18. The sensor arrangementaccording to claim 14, wherein the calibration medium is a liquid whichsubstantially fills the supply line, the return line, and the cuvettesuch that an optical measurement path running between the radiationsource and the radiation receiver traverses the liquid.
 19. The sensorarrangement according to claim 14, wherein the predetermined wavelengthrange is one of ultraviolet, visible and infrared wavelengths.